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Antimicrobial Agents and Chemotherapy, May 2000, p. 1236-1241, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inhibition of Human Rhinovirus-Induced Cytokine Production by AG7088, a Human Rhinovirus 3C Protease Inhibitor

L. S. Zalman,* M. A. Brothers, P. S. Dragovich, R. Zhou, T. J. Prins, S. T. Worland, and A. K. Patick

Agouron Pharmaceuticals, Inc., San Diego, California 92121

Received 6 August 1999/Returned for modification 18 October 1999/Accepted 7 February 2000

Symptom severity in patients with human rhinovirus (HRV)-induced respiratory illness is associated with elevated levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-8. AG7088 is a novel, irreversible inhibitor of the HRV 3C protease. In this study, AG7088 was tested for its antiviral activity and ability to inhibit the production of IL-6 and IL-8 in a human bronchial epithelial cell line, BEAS-2B. Infection of BEAS-2B cells with HRV 14 resulted in the production of both infectious virus and the cytokines IL-6 and IL-8. Treatment of HRV 14-infected cells with AG7088 resulted in a statistically significant (P, <0.05) dose-dependent reduction in the levels of infectious virus as well as IL-6 and IL-8 released into the cell supernatant compared to the results obtained for compound-free infected cells. AG7088 was also able to inhibit the replication of HRV 2 and 16 in BEAS-2B cells. In time-of-addition studies, AG7088 could be added as late as 14 to 26 h after HRV 14 infection of BEAS-2B cells and still result in a statistically significant (P, <0.05) reduction in the levels of infectious virus, IL-6, and IL-8 compared to the results obtained for compound-free infected cells. These findings have implications for the development of an antirhinovirus agent that may not only block virus replication but also diminish symptoms.

* Corresponding author. Mailing address: Department of Virology, Agouron Pharmaceuticals, Inc., 4245 Sorrento Valley Blvd., San Diego, CA 92121. Phone: (619) 622-3062. Fax: (619) 622-5999. E-mail: zalman{at}agouron.com.

Antimicrobial Agents and Chemotherapy, May 2000, p. 1236-1241, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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